Prolyl oligopeptidase inhibition reduces alpha‐synuclein aggregation in a cellular model of multiple system atrophy

Cui, Hengjing; Kilpeläinen, Tommi; Zouzoula, Lydia; Auno, Samuli; Trontti, Kalevi; Kurvonen, Sampo; Norrbacka, Susanna; Hovatta, Iiris; Jensen, Poul Henning; Myöhänen, Timo T.

doi:10.1111/jcmm.16910

Cited by 10 publications

(6 citation statements)

References 55 publications

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“…The results of recent research are consistent with the above possibilities: the addition of human preformed SYN fibrils to mouse OLGs triggered an increase in endogenous SYN, which was critical for its aggregation with TPPP [14]; in agreement with this, in rat OLN-AS7 and human MO3.13 OLG models of MSA, TPPP transfection significantly increased the levels of both SYN mRNA and SYN protein [42]. Moreover, SYN fibrils interfered with the production of proteins associated with neuromodulation and myelination [43].…”

Section: Pathological Interaction Between Tppp and Synsupporting

confidence: 79%

Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP

Oláh,

Norris,

Lehotzky

et al. 2024

Cells

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Neurological disorders such as Parkinsonism cause serious socio-economic problems as there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner of SYN, termed Tubulin Polymerization Promoting Protein (TPPP), which has important physiological and pathological activities such as the regulation of the microtubule network and the promotion of SYN aggregation. The role of TPPP in Parkinsonism is often neglected in research, which we here attempt to remedy. In the normal brain, SYN and TPPP are expressed endogenously in neurons and oligodendrocytes, respectively, whilst, at an early stage of Parkinsonism, soluble hetero-associations of these proteins are found in both cell types. The cell-to-cell transmission of these proteins, which is central to disease progression, provides a unique situation for specific drug targeting. Different strategies for intervention and for the discovery of biomarkers include (i) interface targeting of the SYN-TPPP hetero-complex; (ii) proteolytic degradation of SYN and/or TPPP using the PROTAC technology; and (iii) depletion of the proteins by miRNA technology. We also discuss the potential roles of SYN and TPPP in the phenotype stabilization of neurons and oligodendrocytes.

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Section: Pathological Interaction Between Tppp and Synsupporting

confidence: 79%

Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP

Oláh,

Norris,

Lehotzky

et al. 2024

Cells

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“…PEO is implicated in neurodegeneration and neuroinflammation, and is considered a drug target for the enhancement of memory in dementia [ 182 ]. Inhibition of PEO reduces α-synuclein aggregation in PD [ 183 ]. increases α-synuclein degradation by neural cells [ 184 ].…”

Section: Traditional Chinese Medicinal Formulations Used To Treat Alz...mentioning

confidence: 99%

The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

Melrose

2023

Antioxidants

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Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They have received considerable attention as potential therapeutic agents in biomedicine and have been widely used in traditional complimentary medicine for generations. Such complimentary medical herbal formulations are extremely complex mixtures of many pharmacologically active compounds that provide a therapeutic outcome through a network pharmacological effects of considerable complexity. Methods are emerging to determine the active components used in complimentary medicine and their therapeutic targets and to decipher the complexities of how network pharmacology provides such therapeutic effects. The gut microbiome has important roles to play in the generation of bioactive flavonoid metabolites retaining or exceeding the antioxidative and anti-inflammatory properties of the intact flavonoid and, in some cases, new antitumor and antineurodegenerative bioactivities. Certain food items have been identified with high prebiotic profiles suggesting that neutraceutical supplementation may be beneficially employed to preserve a healthy population of bacterial symbiont species and minimize the establishment of harmful pathogenic organisms. Gut health is an important consideration effecting the overall health and wellbeing of linked organ systems. Bioconversion of dietary flavonoid components in the gut generates therapeutic metabolites that can also be transported by the vagus nerve and systemic circulation to brain cell populations to exert a beneficial effect. This is particularly important in a number of neurological disorders (autism, bipolar disorder, AD, PD) characterized by effects on moods, resulting in depression and anxiety, impaired motor function, and long-term cognitive decline. Native flavonoids have many beneficial properties in the alleviation of inflammation in tissues, however, concerns have been raised that therapeutic levels of flavonoids may not be achieved, thus allowing them to display optimal therapeutic effects. Dietary manipulation and vagal stimulation have both yielded beneficial responses in the treatment of autism spectrum disorders, depression, and anxiety, establishing the vagal nerve as a route of communication in the gut-brain axis with established roles in disease intervention. While a number of native flavonoids are beneficial in the treatment of neurological disorders and are known to penetrate the blood–brain barrier, microbiome-generated flavonoid metabolites (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain the antioxidant and anti-inflammatory potency of the native flavonoid in addition to bioactive properties that promote mitochondrial health and cerebrovascular microcapillary function, should also be considered as potential biotherapeutic agents. Studies are warranted to experimentally examine the efficacy of flavonoid metabolites directly, as they emerge as novel therapeutic options.

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“…Various studies demonstrated that the physiological role of POP is to regulate PP2A; particularly, POP inhibition was recently shown to increase PP2A activity, thereby reducing oxidative stress [ 39 , 40 ]. Moreover, PP2A serves an important role in protection against renal inflammation [ 41 ].…”

Section: Resultsmentioning

confidence: 99%

The Protective Role of Prolyl Oligopeptidase (POP) Inhibition in Kidney Injury Induced by Renal Ischemia–Reperfusion

Casili

Ardizzone

Basilotta

et al. 2021

IJMS

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Ischemia/reperfusion injury (IRI) is a complex pathophysiological process characterized by blood circulation disorder caused by various factors, such as traumatic shock, surgery, organ transplantation, and thrombus. Severe metabolic dysregulation and tissue structure destruction are observed upon restoration of blood flow to the ischemic tissue. The kidney is a highly perfused organ, sensitive to ischemia and reperfusion injury, and the incidence of renal IRI has high morbidity and mortality. Several studies showed that infiltration of inflammatory cells, apoptosis, and angiogenesis are important mechanisms involved in renal IRI. Despite advances in research, effective therapies for renal IRI are lacking. Recently it has been demonstrated the role of KYP2047, a selective inhibitor of prolyl oligopeptidase (POP), in the regulation of inflammation, apoptosis, and angiogenesis. Thus, this research focused on the role of POP in kidney ischemia/reperfusion (KI/R). An in vivo model of KI/R was performed and mice were subjected to KYP2047 treatment (intraperitoneal, 0.5, 1 and 5 mg/kg). Histological analysis, Masson’s trichrome and periodic acid shift (PAS) staining, immunohistochemical and Western blots analysis, real-time PCR (RT-PCR) and ELISA were performed on kidney samples. Moreover, serum creatinine and blood urea nitrogen (BUN) were quantified. POP-inhibition by KYP2047 treatment, only at the doses of 1 and 5 mg/kg, significantly reduced renal injury and collagen amount, regulated inflammation through canonical and non-canonical NF-κB pathway, and restored renal function. Moreover, KYP2047 modulated angiogenesis markers, such as TGF-β and VEGF, also slowing down apoptosis. Interestingly, treatment with KYP2047 modulated PP2A activity. Thus, these findings clarified the role of POP inhibition in AKI, also offering novel therapeutic target for renal injury after KI/R.

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Prolyl oligopeptidase inhibition reduces alpha‐synuclein aggregation in a cellular model of multiple system atrophy

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 10 publications

References 55 publications

Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP

Perspective Strategies for Interventions in Parkinsonism: Remedying the Neglected Role of TPPP

The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

The Protective Role of Prolyl Oligopeptidase (POP) Inhibition in Kidney Injury Induced by Renal Ischemia–Reperfusion

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